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4-sulfur substituted podophyllotoxin derivative and preparation method therefor and use thereof

a technology of podophyllotoxin and substituted sulfur, which is applied in the field of 4-sulfur substituted podophyllotoxin derivatives, can solve the problems of limited clinical applications

Active Publication Date: 2022-02-08
TANG YAJIE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The 4-sulfur substituted derivatives demonstrate improved antitumor activity and reduced toxicity, making them suitable for clinical antitumor drug development with enhanced bioavailability and efficacy compared to traditional podophyllotoxin.

Problems solved by technology

However, the clinical applications are limited due to their strong toxic side effects and poor bioavailability.

Method used

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  • 4-sulfur substituted podophyllotoxin derivative and preparation method therefor and use thereof
  • 4-sulfur substituted podophyllotoxin derivative and preparation method therefor and use thereof
  • 4-sulfur substituted podophyllotoxin derivative and preparation method therefor and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1 synthesis

and Purification of 4-β-S-(4-trifluoromethylpyridin-2)-podophyllotoxin (Compound 1)

[0032](1) Synthesis of 4-β-S-(4-trifluoromethylpyridin-2)-podophyllotoxin:

[0033]414 mg (1 mmol) of podophyllotoxin and 179 mg (1 mmol) of 4-trifluoromethylpyridin-2-thiol were dried under vacuum for 1 h, 15 ml of trifluoroacetic acid was added as a solvent in an ice bath, followed by stirring at atmospheric pressure for 1-3 h, chloroform acetone was used as a developing solvent to monitor the reaction endpoint; the reaction system was added into 20-50 times of volume of deionized water, followed by filtering, and a filter cake was collected, washed and dried to obtain a crude product.

[0034](2) Separation and purification of 4β-S-(4-trifluoromethylpyridin-2)-podophyllotoxin: the separation and purification were performed using silica gel column chromatography and gel column chromatography:

[0035](A) A separation was performed through a normal phase silica gel column (normal phase silica gel: China Qingd...

example 2 synthesis

and Purification of 4-β-S-(4-trifluoromethylpyridin-2)-4demethylepipodophyllotoxin (Compound 2)

[0039](1) Synthesis of 4-β-S-(4-trifluoromethylpyridin-2)-4demethylepipodophyllotoxin: 400 mg (1 mmol) of 4demethylepipodophyllotoxin and 179 mg (1 mmol) of 4-trifluoromethylpyridin-2-thiol were dried under vacuum for 1 h, the mixture was stirred under vacuum for 1-3 h with 15 ml of trifluoroacetic acid as a solvent in an ice bath, and the reaction end point was detected with chloroform acetone as a developing solvent. The reaction system was added into 20-50 times of volume of deionized water and filtered; a filter cake was collected, washed and dried to obtain a crude product.

[0040](2) Separation and Purification of 4-β-S-(4-trifluoromethylpyridin-2)-4demethylepipodophyllotoxin:

[0041]the separation and purification were performed using silica gel column chromatography and gel column chromatography in the same manner as in Example 1.

[0042]Compound 2 4-β-S-(4-trifluoromethylpyridin-2)-4dem...

example 3 synthesis

and Purification of 4-β-S-(4-trifluoromethylpyrimidin-2)-podophyllotoxin (Compound 3)

[0044](1) Synthesis of 4-β-S-(4-trifluoromethylpyrimidin-2)-podophyllotoxin: 414 mg (1 mmol) of podophyllotoxin and 1472 mg (8 mmol) of 4-(trifluoromethyl)-2-mercaptopyrimidine were dried under vacuum for 1 h, the mixture was stirred under vacuum for 1-3 h with 15 ml of trifluoroacetic acid as a solvent in an ice bath, and the reaction end point was detected with chloroform acetone as a developing solvent. The reaction system was added into 20-50 times of volume of deionized water and filtered; a filter cake was collected, washed and dried to obtain a crude product.

[0045](2) Separation and purification of 4-β-S-(4-trifluoromethylpyrimidin-2)-podophyllotoxin: the separation and purification were performed using silica gel column chromatography and gel column chromatography in the same manner as in Example 1.

[0046]Compound 3 4-β-S-(4-trifluoromethylpyrimidin-2)-podophyllotoxin:white powder, C27H23F3N2...

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Abstract

Disclosed are a 4-sulfur substituted podophyllotoxin derivative and a synthetic method therefor and the use thereof. In the present invention, introducing heteroaromatic compounds with rigidity, such as 4-trifluoromethylpyridin-2-thiol, 4-trifluoromethyl-2-mercaptopyrimidine, and para-fluorothiophenol, respectively as substituent groups to position 4 of C ring of a podophyllotoxin or 4demethylepipodophyllotoxin, obtaining a podophyllotoxin derivative as shown in formula (V) with a significantly improved antitumour activity and reduced toxic side effects. Experiments of in vitro tumour cell activity inhibition indicate that the antitumour activity of the compound as shown in formula (V) of the present invention is significantly improved compared to that of the podophyllotoxin or 4demethylepipodophyllotoxin.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation of International Application No. PCT / CN2018 / 089832 filed Jun. 4, 2018, which claims priority from Chinese Patent Application No. 201710912793.8 filed Sep. 22, 2017, all of which are incorporated herein by reference.TECHNICAL FIELD[0002]The invention belongs to the field of podophyllotoxin derivatives, in particular to 4-sulfur substituted podophyllotoxin derivatives and a preparation method therefor, and the invention also relates to use of the 4-sulfur substituted podophyllotoxin derivatives in the preparation of antitumor drugs.BACKGROUND ART[0003]The structures of podophyllotoxin and demethylepipodophyllotoxin are shown as formula (I) and (II) in FIG. 1. Podophyllotoxin and 4demethylepipodophyllotoxin are natural active lead compounds with broad-spectrum antitumor activity extracted from podophyllotoxin plants (e.g. Sinopodophyllum hexandrum, Dickinsia hydrocotyloides, Dysosma versipellis, etc....

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D493/04A61P35/00C07D471/04
CPCC07D493/04A61P35/00C07D471/04C07D491/04
Inventor TANG, YAJIEZHAO, WEI
Owner TANG YAJIE
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